Chemical process

ABSTRACT

Saturated organic compounds containing a hydrogen atom bound to a tertiary carbon atom may be electrophilically fluorinated by reaction with an electrophilic fluorinating agent such as molecular fluorine or trifluoromethyl hypofluorite under conditions whereby the formation of free fluorine radicals is suppressed, e.g. by the presence of a free radical inhibitor such as oxygen or nitrobenzene, the reactants being substantially homogeneously dispersed in a liquid medium, e.g. a solvent medium such as fluorotrichloromethane or chloroform/fluorotrichloromethane, so that the said hydrogen atom is electrophilically replaced by a fluorine atom. The fluoroination is highly selective and, in the case of complex substrates such as saturated steroids which contain a number of tertiary C--H bonds, may be substantially completely confined to replacement of the hydrogen atom at the tertiary carbon atom which has the highest electron density about the C--H bond. The electron density and thus the direction of the fluorination may be controlled by appropriate selection of substituent groupings in the substrate molecule. 
     Novel 14α-fluorosteroids are also disclosed, including compounds having valuable androgenic or progestational activity and useful synthetic intermediates.

This invention relates to a novel process for the introduction offluorine into organic compounds and to novel fluorinated products whichmay be obtained thereby.

The introduction of fluorine into organic structures is known to givevaluable results in many fields. Thus in the field of steroids, forexample, introduction of fluorine, e.g. at the 9- or 6-positions, hasbeen found to enhance physiological activity. In general the fact thatfluorine and hydrogen are similar in size but very different inelectronegativity means that replacement of hydrogen by fluorine in abiologically active compound will change or potentiate the activity ofthe compound.

In previously proposed methods for fluorination at saturated carbonatoms it has been thought necessary to employ free fluorine radicals.Consequently, even when reagents capable of electrophilic fluorination,for example molecular fluorine or trifluoromethyl hypofluorite, havebeen used, the system has been irradiated with ultraviolet or visiblelight, if necessary in the presence of an initiator such as benzoylperoxide, to ensure the production of free radicals. Metal and metalsalt catalysts have also been used in such fluorination reactions toinitiate free radical formation. An inherent disadvantage of thesefluorination reactions, by virtue of the free radical mechanism by whichthey proceed, is that the specificity and selectivity of thefluorination is generally low. Thus, for example, fluorination of asensitive substrate such as a saturated steroid using free radicalconditions tends to lead to the formation of a complex mixture offluorinated products, so that isolation of a particular fluorinatedproduct may require complicated separation techniques and normallyaffords only a comparatively low yield of the desired product.

We have found that organic compounds may in fact by fluorinated atsaturated carbon atoms by an electrophilic mechanism on treatment withan electrophilic fluorinating agent if steps are taken to suppresscompeting free radical reactions. The electrophilic fluorinationreaction is inherently more directional then free radical fluorinations,being strongly influenced by the electron densities about individualbonds in the fluorination substrate, as evidenced by, for example, thefact that the reaction is substantially completely confined to thefluorination of tertiary saturated carbon atoms. Thus fluorination ofsaturated organic substrates (as hereinafter defined) by this techniquegenerally leads to a cleaner, more specific and more selective reactionthan do the known free radical fluorination techniques.

According to one aspect of the present invention, therefore, we providea process for the electrophilic fluorination of a saturated organiccompound containing a hydrogen atom bound to a tertiary carbon atomwhich comprises reacting together the said compound and an electrophilicfluorinating agent substantially homogeneously dispersed in a liquidmedium in the presence of a substance suppressing free radical reactions(hereinafter referred to as a "free radical inhibitor"), wherebyformation of free fluorine radicals is suppressed and the said hydrogenatom is electrophilically replaced by a fluorine atom, and recoveringthe thus-obtained tertiary organic fluoride.

By the term "saturated organic compound" as used in this specificationwe mean a compound wherein all the carbon-carbon linkages are saturatedor wherein any carbon-carbon multiple bonds are substantially completelydeactivated against electrophilic fluorination under the reactionconditions employed, e.g. by substitution with one or more stronglyelectron-withdrawing groups; the compound may contain multiple bonds toatoms other than carbon, e.g. in substitutent groupings, provided thatthese multiple bonds do not react to a significant extent with thefluorinating agent. The term "tertiary carbon atom" designates a carbonatom which is bonded to three other carbon atoms and which is alsobonded to a hydrogen atom.

The electrophilic fluorinating agent used in the process of theinvention may, for example, be a hypofluorite wherein the fluoroxy groupis bonded to an inert electron attracting group, which may be eitherinorganic or organic. Suitable inorganic hypofluorites includefluorosulphur hypofluorites such as pentafluorosulphur hypofluorite.Organic hypofluorites which may be used include lower (e.g. C₁₋₆)fluoroalkyl hypofluorites, the fluoroalkyl portions of which preferablycontain at least two fluorine atoms per carbon atom. Examples of suchorganic hypofluorites include trifluoromethyl, perfluoropropyl,perfluoroisopropyl, perfluoro-t-butyl, monochlorohexafluoropropyl andperfluoro-t-pentyl hypofluorites and difluoroxy compounds such as1,2-difluoroxytetrafluoroethane and difluoroxydifluoromethane. The useof trifluoromethyl hypofluorite is particularly preferred by virtue ofits good selectivity and comparative ease of handling.

Molecular fluorine may also be employed as the electrophilicfluorinating agent in the process of the invention. Where fluorine isused in this way it is preferably either diluted with an inert gas suchas nitrogen or argon, the concentration of fluorine in the resulting gasmixture conveniently being in the range 1-20% v/v, e.g. 3-16% v/v, or isintroduced into the reaction system undiluted but at reduced pressure,e.g. less than 100 mm Hg, in order to moderate the reaction andfacilitate control.

The fluorination is normally conducted in a liquid medium which is asolvent medium for the saturated organic compound to be fluorinated. Thesolvent need not be completely inert to the reaction conditions and inmany cases will act as a free radical inhibitor as described in moredetail hereinafter. Suitable solvents include lower alkanoic acids suchas acetic acid; fluorinated lower alkanoic acids such as trifluoroaceticacid; fluorinated or fluorinated and chlorinated lower alkanes such asfluorotrichloromethane, chlorotrifluoromethane, dichlorodifluoromethaneor 1,1,2-trichlorotrifluoroethane; fluorinated lower alkanols such as2,2,2-trifluoroethanol; hydrates, e.g. the sesquihydrate, ofhexafluoroacetone; nitriles such as acetonitrile; sulphones, e.g.di(lower alkyl)sulphones such as dimethylsulphone or cyclic sulphonessuch as sulpholane; and lower nitroalkanes such as nitromethane (thequalifiaction "lower" is used in this specification to designatemolecules or groups containing up to 6 carbon atoms). Partiallychlorinated lower alkanes such as chloroform or methylene chloride mayalso be employed as solvent, although such chloroalkanes have a tendencyto react with the fluorinating reagent, which may therefore have to beused in excess to achieve optimum yields of the desired fluorinatedproduct. Mixtures of solvents, e.g. fluorotrichloromethane andchloroform, may be used if desired. Cosolvents, e.g. water, loweralkanols such as methanol or ethanol, and cyclic ethers such as dioxanor tetrahydrofuran, may also be employed. Some displacement of the newlyintroduced fluorine atoms by solvent molecules may occur when solventssuch as alkanols and carboxylic acids, which contain nucleophiliccentres, are used, although this tendency is reduced if steps are taken,e.g. as described hereinafter, to remove the hydrogen fluoride normallyformed as a by product of the fluorination reaction.

We have found that the efficiency of the fluorination reaction isgreatly impaired unless steps are taken to ensure that the reactionmixture remains essentially homogeneous throughout the course of thereaction. It will be appreciated that selection of a liquid medium whichis a solvent for the saturated organic compound will assist in achievingeven dispersion of the saturated organic compound in the reactionmixture. Fluorinating agents such as gaseous or volatile liquidhypofluorites or fluorine/inert gas mixtures are advantageously passedinto the reaction mixture in gaseous form in such a way as to ensuregood dispersion of the gas within the solution, for example by passagethrough a sintered dispersion tube or a perforated disc or foil. Thereaction mixture is also desirably stirred or otherwise agitated toenhance dispersion of the fluorinating agent. Hypofluorite reagents aregenerally highly soluble in the commonly employed reaction media, sothat adequate dispersion of these reagents can be effected comparativelyeasily. Elemental fluorine has a substantially lower solubility,however, so that efficient dispersion of the fluorine/inert gas mixtureas it enters the reaction mixture and vigourous agitation of the mixtureare required to produce the desired degree of homogeneity.

Alternatively the fluorinating agent may be employed in solution, e.g.in one of the solvents listed above, or in liquid form, e.g. in the caseof a liquid hypofluorite having comparatively low volatility; mixing ofthis fluorinating agent solution with the reaction mixture containingthe saturated organic compound is desirably accompanied by vigorousstirring or other agitation to enhance dispersion of the fluorinatingagent.

Where the fluorination is conducted in a solvent medium theconcentration of the reactants in the reaction solution is desirablykept comparatively low in order to ensure substantially homogeneousreaction conditions. Thus, for example, we prefer to employcomparatively dilute solutions of the saturated organic compound, e.g.solutions containing 4-500 millimoles per liter of said compound.Similarly, where a gaseous hyopfluorite reagent is employed it may beadvantageous to admix this with an inert gaseous diluent such asnitrogen before its introduction into the reaction solution. Thehomogeneity of the reaction solution is further enhanced if thefluorinating agent is added slowly over a period of time, e.g. 2-24hours, to the solution of the saturated organic compound.

The reaction temperature is preferably kept relatively low, the optimumtemperature for a given reaction depending on, inter alia, thereactivity of the fluorinating agent. Hypofluorites, for example, mayconveniently be employed at temperatures in the range -78° to +40° C.;more reactive hypofluorites such as pentafluorosulphur hypofluorite maybe used at lower temperatures within this range, whereas milderfluorinating agents such as trifluoromethyl hypofluorite may be employedat higher temperatures, e.g. in the range -25° to +25° C. Reactionsinvolving molecular fluorine are generally conducted at somewhat lowertemperatures, e.g. in the range -100° to 0° C., conveniently at from-80° to -75° C.

As indicated above, the fluorination is conducted in the presence of afree radical inhibitor in order to suppress competing free radicalreactions which would detract from the selectivity and specificity ofthe electrophilic fluorination reaction. We have found oxygen to be avery effective free radical inhibitor for this purpose. In some casesoxygen will already be present in sufficient quantity in the reactionsystem, for example as a contaminant of nitrogen used to dilute agaseous fluorinating agent or in solution in the reaction solvent, toinhibit any radical reactions; alternatively, sufficient radicalinhibition may be achieved if the reaction is conducted in the presenceof air, for example using a partially open reaction vessel. In otherinstances it may be desirable actually to introduce oxygen or air intothe reaction system to obtain satisfactory radical inhibition.

Other free radical inhibitors which may be employed includenitro-substituted aromatic hydrocarbons, for example nitrobenzene orm-dinitrobenzene, and quinones, for example benzoquinone.

The amount and nature of the free radical inhibitor used in a givenfluorination reaction will to some extent depend on the particularelectrophilic fluorinating agent employed. Thus, for example,hypofluorites such as trifluoromethyl hypofluorite are somewhat moreprone to free radical formation than molecular fluorine and may requirelarge quantities of inhibitor or the use of more potent inhibitors tosuppress fully any radical reactions.

As indicated above, the reaction solvent may in certain cases act as afree radical inhibitor, as may any cosolvent used therewith. Thus, forexample, solvents or cosolvents containing one or more reactive hydrogenatoms bound to carbon, for example partially chlorinated hydrocarbonssuch as chloroform or methylene chloride or cyclic ethers such astetrahydrofuran, will suppress free radical reactions in cases whereinhypofluorites are employed as the fluorinating agent, although thedegree of inhibition achieved in such solvents may be somewhat less thanthat obtained by the use of the above-described free radical inhibitorssuch as oxygen, nitrobenzene and benzoquinone. In cases where molecularfluorine is employed as the fluorinating agent, most solvents will haveat least a partial inhibitory effect on any competing free radicalreactions. This will generally be complemented by the inhibitory effectof traces of oxygen which will normally be present in the reactionsystem if it has not been purposely excluded, so that in many casessolution reactions using, for example, a fluorine/nitrogen gas mixtureas the fluorinating agent may not in fact require the addition of aseparate free radical inhibitor.

A side reaction which may accompany the fluorination process of theinvention comprises elimination of the newly-introduced fluorine atomtogether with a hydrogen atom from an adjacent carbon atom, withconsequent formation of a carbon-carbon double bond. The double bond maysubsequently react with the fluorinating agent leading to the formationof a range of fluorinated by-products, which may be unwanted. Theelimination is catalysed by hydrogen fluoride, which is in most cases aby-product of the fluorination process; the elimination is alsoeffectively autocatalytic since it is necessarily accompanied by theformation of hydrogen fluoride.

We have found that this side reaction may be suppressed to a substantialdegree if the fluorination process is carried out in the presence of asubstance which will bind or absorb hydrogen fluoride, for example aweak base (e.g. an alkali metal salt of an organic acid, for example alower alkanoic acid such as acetic acid or a halogenated, preferablyfluorinated, lower alkanoic acid such as trifluoroacetic acid, or ananhydrous alkali metal fluoride such as sodium or potassium fluoride), adried and activated molecular sieve or an organosilicon compound whichcontains a bond to silicon that is easily cleaved by hydrogen fluorideto give a silyl fluoride and which is unreactive to the fluorinatingagent (e.g. a siloxane such as hexamethyldisiloxane, a silyl ether suchas methyl trimethylsilyl ether, a silyl ester such as trimethylsilylacetate or a silylamide such as N,O-bis(trimethylsilyl)trifluoroacetamide). We prefer to use weak bases such as sodiumtrifluoroacetate or sodium or potassium fluoride as a basic hydrogenfluoride binding agent when a hypofluorite is employed as thefluorinating agent since stronger bases such as sodium or potassiumacetate tend to promote decomposition of the hypofluorite, although suchstronger bases are tolerated when, for example, elemental fluorine isemployed as fluorinating agent.

Crude reaction products obtained by the fluorination process of theinvention may also be prone to decompose by elimination of hydrogenfluoride in a similar manner to that described above, particularly whena hypofluorite fluorinating agent has been employed, the autocatalyticdecomposition being initiated by hydrogen fluoride formed from thebreakdown of impurities such as carbonyl difluoride. It may therefore beadvantageous, especially where no base has been added previously, to adda base, for example a tertiary organic base such as pyridine ortriethylamine, to the crude reaction product to bind any hydrogenfluoride which is liberated and so stabilise the desired fluorinatedproduct; such treatment is particularly desirable when there is to beany delay in the isolation and purification of the desired product.

Saturated organic compounds which may be fluorinated in accordance withthe process of the invention include compounds of formula ##STR1##wherein either (A) R¹, R² and R³ (which may be the same or different)are each selected from alkyl groups containing up to 30 carbon atoms,preferably 1-20 carbon atoms, e.g. methyl, ethyl, propyl, butyl, octyl,decyl, stearyl and eicosyl; saturated mono- and polycyclic (includingbicyclic) cycloaliphatic groups containing up to 30 carbon atoms, morepreferably 5-25 carbon atoms, and optionally containing one or moreheteroatoms selected from O,N and S, e.g. monocyclic cycloalkyl groupssuch as cyclopentyl or cyclohexyl, polycyclic (including bridged)cycloalkyl groups such as adamantyl or norbornyl, fused polycyclicstructures such as saturated steroidal groups, sugar groups, andtetrahydrofuranyl and tetrahydrothienyl groups; and any of these groupssubstituted by one or more halogen atoms (i.e. fluorine, chlorine,bromine and iodine atoms), and/or oxo, cyano, nitro, hydroxy, protected(e.g. esterified) hydroxy (e.g. lower alkanoyloxy such as acetoxy,halogenated lower alkanoyloxy such as trichloroacetoxy ortrifluoroacetoxy, nitrooxy, or nitro-substituted benzoyloxy such asp-nitrobenzoyloxy or 2,4-dinitrobenzoyloxy), lower alkoxy (e.g. methoxyor ethoxy), mercapto, sulphino, lower alkylthio (e.g. methylthio), loweralkylsulphinyl (e.g. methylsulphinyl), lower alkylsulphonyl (e.g.methylsulphonyl), acyl (e.g. lower alkanoyl such as acetyl), acylamino(e.g. trifluoroacetamido, N,N-diacylamino (e.g. phthalimido, succinimidoor N,N-diacetylamino) or di(lower alkyl) amino (e.g. dimethylamino)groups; or (B) R¹ has any of the above-defined meanings and R² and R³together with the attached carbon atom form an unsubstituted orsubstituted saturated mono- or polycyclic cycloaliphatic group asdefined in (A) above; or (C) R¹, R² and R³ together with the attachedcarbon atom form an unsubstituted or substituted polycycliccycloaliphatic group as defined in (A) above.

As indicted above, the organic substrate may contain carbon-carbonmultiple bonds provided that these are substantially completelydeactivated against electrophilic fluorination under the reactionconditions employed, e.g. by substitution with one or more stronglyelectron-withdrawing groups; in general multiple bonds present inaromatic groups are more susceptible to such deactivation than arealiphatic multiple bonds. Thus the compounds of formula I may containaromatic groups (e.g. phenyl) substituted by one or more stronglyelectron-withdrawing groups such as nitro, sulphonyl (e.g. loweralkylsulphonyl such as methylsulphonyl), esterified sulphonyl (e.g.lower alkoxysulphonyl such as methoxysulphonyl) or amido, or by adivalent electron-withdrawing group such as an amidodicarbonyl group(e.g. so that the substituted aromatic group forms a phthalimido group).Such aromatic groups may not be totally inert to the fluorinationreaction, but will in general react substantially more slowly thansaturated tertiary carbon atoms. The aromatic groups may for example bepresent as or in protecting groups used to substitute and deactivatereactive groups such as amino or hydroxy present in any of R¹, R² andR³, as described in greater detail hereinafter. Since such protectinggroups are normally removed at a later stage of the reaction sequence,partial fluorination of the aromatic group in such circumstances willnot affect the nature of the final product.

Reactive groups such as primary or secondary amino which may be presentin fluorination substrates as substituents or in nitrogen-containingheterocyclic systems should be protected prior to fluorination, forexample by acylation to yield an amide derivative or by reaction with astrong acid such as fluoroboric, sulphuric or hexafluorophosphoric acidto yield a salt. Simple carboximides and sulphonamides will tend toundergo N-fluorination under the conditions employed for theelectrophilic fluorination, so that protecting amide groups should beformed from strongly deactivating (i.e. electron withdrawing) acylmoieties such as trifluoroacetyl, or the amino group (if primary) shouldbe protected as an N,N-diacylamino groups (e.g. an N,N-phthaloyl-,N,N-succinoyl- or N,N-diacetyl-amino group), if such N-fluorination isundesired.

Mercapto and sulphide groups present in fluorination substrates aresusceptible to attack by the fluorinating agent, leading ultimately toformation of a sulphide or sulphoxide group. Where it is desired toavoid such side reactions any mercapto or sulphide groups present in thesubstrate may effectively be protected by oxidation to sulphoxide or,more preferably, sulphone groups prior to the fluorination.

It may also be advantageous to protect any hydroxy substituents, e.g. byesterification, prior to fluorination. The use of esters derived fromperfluoro lower alkanoic acids such as trifuoroacetic acid may be ofvalue in this respect since such esterification will increase the polareffect of the hydroxyl group and may thus influence the direction of thefluorination reaction as described hereinafter. Ester groups derivedfrom perfluorinated acids such as trifluoroacetic acid may also readilybe removed after the fluorination by hydrolytic or hydrogenolyticcleavage. Other useful protecting ester groups include inorganic groupssuch as nitro and ester groups derived from lower aliphatic acids (e.g.lower alkanoic and halogenated lower alkanoic acids such as acetic ortrichloroacetic acid) and aromatic acids wherein the aromatic ringcarries one or more strongly electron-withdrawing substituents (e.g.p-nitrobenzoic acid or 2,4-dinitrobenzoic acid).

Where it is desired to fluorinate a saturated carbon atom in a substratecontaining a carbon-carbon double bond the double bond may effectivelybe "protected" by halogenation of the substrate to yield an α,β-dihaloderivative, e.g. by treatment with molecular bromine in a solvent suchas acetic acid, by treatment with dioxan dibromide in a solvent such asether or carbon tetrachloride: chloroform, or by treatment withmolecular chlorine in a solvent such as benzene. A preferred brominationtechnique comprises reaction with excess dioxan dibromide in carbontetrachoride: chloroform (ca 2:1) in the dark in the presence ofpotassium carbonate. The double bond may subsequently be regenerated bydehalogenation of the compound, e.g. by treatment with zinc and aceticacid or ammonium acetate.

As indicated above, the electrophilic nature of the fluorination processof the invention causes the direction, and similarly the rate, of thefluorination to be influenced strongly by the electron density aboutindividual bonds in the reaction substrate. One consequence of this isthat fluorination in accordance with the invention effectively occursonly at tertiary carbon atoms. This behavior may be contrasted with thatobserved in free radical fluorination reactions where, for example,secondary carbon atoms are fluorinated at not unduly dissimilar rates totertiary carbon atoms (tertiary carbon atoms typically reacting at 2-4times the rate for secondary carbon atoms). The process of the inventionis therefore of particular value in the selective fluorination oftertiary carbon atoms in saturated organic substrates.

It will be appreciated that some of the possible groups listed above forR¹, R² and R³ contain a CH grouping capable of being fluorinated by theelectrophilic mechanism of the process of the invention. It is anadvantage of the process, however, that the fluorinating agent willattack predominantly the site having the highest electron density, andsuch sites can normally be identified in the substrate on a conventionaltheoretical basis. A substrate having more than one CH group may, ofcourse, be represented in terms of R¹ R² R³ CH in different ways; ingeneral the preferred representation should be that in which the CHgroup shown possesses a higher electron density than any other CH grouppresent.

It will similarly be appreciated that where, for example, a substratecontains two tertiary carbon atoms which have similar electron densitiesabout the respective C--H bonds, fluorination may occur at either ofthese tertiary carbon atoms to give a mixture of two monofluorinatedproducts. In general the incidence of difluorinated products isnegligible in such circumstances, since the introduction of a fluorineatom at one tertiary carbon atom will in many instrances deactivate theother tertiary carbon atom or atoms as regards further electrophilicfluorination.

An example of the selective fluorination of a tertiary carbon atom usingthe process of the invention is afforded by the fluorination ofadamantane by treatment with, for example, trifluoromethyl hypofluoritein the presence of air. The adamantane is fluorinated cleanly andexclusively at the tertiary 1-position, no significant fluorinationtaking place at the secondary 2-position under the conditions requiredfor reaction at the 1-position. Introduction of the electronegativefluoro substituent at the 1-position effectively deactivates theremaining tertiary carbon atoms in the molecule so that no electrophilicreaction is observed at these carbon atoms unless more vigorousconditions are employed.

It will be apparent from the above that the presence of polarsubstituents in the saturated organic substrate will significantlyaffect the course of the electrophilic fluorination by virtue of theirinfluence on the electron density in the substrate molecule. Thus, forexample, the rate of the fluorination reaction will generally bedecreased by the presence of an electron withdrawing group in thevicinity of the tertiary carbon reaction center. This may be illustratedby the fluorination, e.g. using trifluoromethyl hypofluorite in thepresence of air, of 1-trifluoroacetamidoadamantane, which reacts atabout half the rate of adamantane itself, to give the tertiary 3-fluoroderivative. 1-Trifluroacetoxyadamantane is fluorinated even more slowlyunder such conditions, so that a mixture of adamantane and1-trifluoroacetoxyadamantane may be treated with, for example, afluorine/nitrogen gas mixture containing a small proportion of oxygen topromote selective fluorination of the unsubstituted adamantane componentonly.

This deactivating effect of electron withdrawing substituents may beemployed to advantage in directing the fluorination in cases wherecomplex substances containing several non-equivalent tertiary carbonatoms are required to be fluorinated at a single carbon atom, forexample in the preparation of monofluorinated steroid derivatives.

Thus a saturated steroid such as 5α-androstane ##STR2## has in principlefour tertiary carbon atoms, at the 5-, 8-, 9- and 14-positionsrespectively, which might be expected to undergo ready electrophilicfluorination in accordance with the process of the invention, althoughthe 8-position carbon atom is in fact somewhat unreactive to suchfluorination by virtue of the attached hydrogen atom being on the β-faceof the molecule and thus being screened by the C₁₈ and C₁₉ methylgroups. It is possible, however, to direct the fluorinationsubstantially exclusively to any of the other tertiary centers by use ofappropriately substituted steroid starting materials.

Thus, for example, electrophilic fluorination of a saturated steroid inwhich there are electron-withdrawing substituents present on the A- andD- rings, for example a compound of formula ##STR3## [where R⁴represents protected (e.g. esterified, etherified or silylated] hydroxy(α- or β-) and R⁵ represents hydrogen or R⁴ and R⁵ together represent aketo or protected keto (e.g. ketal) group, and R⁶ and R⁷ each representhydrogen, or R⁴ and R⁶ together represent a 3,5-cyclo linkage, R⁵represents hydrogen and R⁷ represents protected hydroxy (α- or β-); R⁸represents hydrogen, methyl or protected hydroxy (α- or β-); R⁹represents hydrogen, hydroxy or protected hydroxy and R¹⁰ representsacetyl or substituted acetyl (e.g. hydroxyacetyl or, more preferably,protected hydroxyacetyl, e.g. esterified hydroxyacetyl such asacetoxyacetyl), or R⁹ represents hydrogen and R¹⁰ represents protected(e.g. esterified) hydroxy, or R⁹ and R¹⁰ together represent a ketogroup] such as 3β, 17β-di(trifluoroacetoxy)-5α-androstane, leads toformation of the corresponding 9α-fluoro derivative, e.g. having theformula ##STR4## (where R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as definedabove), the 5- and 14-positions being deactivated to electrophilicattack by the proximity of the electron withdrawing substituents on theA- and D-rings, e.g. at the 3- and 17-positions respectively, and the8-position being sterically hindered.

It may also be possible to obtain a proportion of the 14α-fluoroanalogue of a compound (IV) in the reaction product, especially if astarting material (III) in which R⁹ and R¹⁰ have comparatively lowelectron-withdrawing properties (e.g. a compound wherein R⁹ is hydrogenor hydroxy and R¹⁰ is acetyl or substituted acetyl such asacetoxyacetyl, or R⁹ or R¹⁰ together represent a keto group) isselected.

When a starting material (III) in which R⁷ is a protected hydroxy groupis employed and a 9α-fluoro product is desired, the group R⁷ ispreferably one which has comparatively low electron-withdrawingproperties (e.g. a lower alkanoyloxy group such as acetoxy) and so doesnot effect undue deactivation of the 9α-position with regard toelectrophilic reaction.

The electrophilic fluorination of a saturated steroid may similarly bedirected substantially exclusively to the 14α-position by selection of astarting material in which the A- and B-rings are substituted byelectron-withdrawing atoms or groups. Thus, for example, electrophilicfluorination of a compound of formula ##STR5## [where R¹¹ representsprotected hydroxy (α- or β-) and R¹² represents hydrogen or R¹¹ and R¹²together represent a keto or protected keto group, R¹³ representshydrogen and R¹⁴ and R¹⁵ both represent halogen (e.g. chloro or bromo),or R¹⁴ together with R¹³ or R¹⁵ represents an epoxy group, the remainingR¹³ or R¹⁵ representing hydrogen, or R¹¹ and R¹⁴ together represent a3,5-cyclo linkage, R¹² and R¹³ each represent hydrogen, and R¹⁵represents protected hydroxy (e.g. esterified hydroxy such as acetoxy);and R¹⁶ represents oxo, acetyl or protected hydroxy (e.g. esterifiedhydroxy such as acetoxy)] such as 5α,6β-dibromo-3β-trifluoroacetoxy-androstan-17-one or 5α,6β-dibromo-3β-trifluoroacetoxypregnan-20-one, leads to formation of thecorresponding 14α-fluoro derivative having the formula ##STR6## (whereR¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are as defined above), the 9-positionbeing deactivated by the electronegative substituents present at the 5-and/or 6-positions.

It may also be possible to obtain a proportion of the 9α-fluoro analogueof a compound (VI) in the reaction product, especially if a startingmaterial (V) in which R¹⁴ and R¹⁵ have comparatively lowelectron-withdrawing properties (e.g. a compound in which R¹¹ and R¹⁴form a 3,5-cyclo linkage, R¹² and R¹³ represent hydrogen, and R¹⁵ isacetoxy) is selected.

Steroids having a 17β-hydrocarbon group possess a nuclear tertiaryhydrogen atom at the 17α-position, but this position is less susceptibleto fluorination than the 9- or 14-positions. When, however, there areelectron withdrawing substituents on the B-ring, and preferably also theA-ring, the 9- and 14- positions are deactivated and the 17α-position isfluorinated (unless there is a nearby electron withdrawing group, suchas a 20-keto group). Thus electrophilic fluorination in accordance withthe invention of a compound of formula ##STR7## (where R¹¹, R¹², R¹³,R¹⁴ and R¹⁵ are as defined above and R¹⁷ is a saturated hydrocarbongroup e.g. containing 2-12 carbon atoms, for example the--CH(CH₃).(CH₂)₃.CH(CH₃)₂ side chain characteristic of cholesterol) suchas 5α,6β-dichloro-3β-trifluoroacetoxycholestane, leads to formation ofthe corresponding 17α-fluoro derivative, e.g. having the formula##STR8## (where R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁷ are as defined above),in view of the deactivation of the 9- and 14-positions. The tertiaryhydrogen atoms in the side chain are less active, as is usual, than anyof the tertiary hydrogen atoms in the ring-structure.

Where any of R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁵ and R¹⁶ in formulae(II)-(VIII) represent or contain protected hydroxy groups theseprotected hydroxy groups may, for example, be esterified hydroxy groupsas described above (e.g. lower alkanoyloxy such as acetoxy, halogenatedlower alkanoyloxy such as trichloroacetoxy or trifluoroacetoxy,nitroaroyloxy such as p-nitrobenzoyloxy or 2,4-dinitrobenzoyloxy, andinorganic ester groups such as nitrooxy); etherified hydroxy groups suchas lower alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy ort-butoxy), aralkoxy (e.g. phenyl lower alkoxy such as benzyloxy,diphenylmethoxy or triphenylmethoxy) or aryloxy (e.g. phenoxy); orsilyloxy groups such as lower alkyl-, aralkyl- (e.g. phenyl loweralkyl-) or aryl-(e.g. phenyl-) substituted silyloxy [e.g. tri(loweralkyl) silyloxy such as trimethylsilyloxy]. Such protecting groups maybe introduced by, for example, conventional methods; thus hydroxy groupsmay be silylated by reaction of the hydroxy compound with an appropriatehalosilane or silazane, e.g. a tri(lower alkyl) silyl halide or hexa(lower alkyl) disilazane.

Where R⁴ and R⁵ in formulae III and IV or R¹¹ and R¹² in formulae V-VIIItogether represent a ketal group they may, for example, each be loweralkoxy such as methoxy or ethoxy or may together represent a loweralkylenedioxy group such as ethylenedioxy.

The above described behaviour of steroid substrates in the process ofthe invention, which may readily be predicted on a conventionaltheorectical basis, is in total contrast to that observed in the freeradical fluorination of such steroids, when all the tertiary centres areattached equally and indiscriminately.

A further advantage of the process of the invention in the fluorinationof complex substrates such as steroids is that the reaction proceedswith retention of configuration. While we do not wish to be bound bytheoretical considerations it would appear that the fluorinationproceeds by an S_(E) 2 mechanism involving formation of pentacoordinatecarbonium ions by insertion of "F^(+") into the tertiary C--H bond,since other reactions of this type are known to lead to retention ofconfiguration.

It will be appreciated from the above that the process of the inventionpossesses wide-ranging applications in the fluorination of saturatedorganic compounds containing tertiary carbon atoms. Thus, for example,the process may be used to prepare fluorinated adamantane derivativeswhich are valuable intermediates in the synthesis of compoundspossessing antiviral and/or spasmolytic activity and which may thus beused in, for example, combatting influenza viruses and treatingParkinson's disease. Fluorinated adamantane derivatives and othertertiary fluorinated saturated aliphatic hydrocarbons which may beprepared in accordance with the invention have also been shown to act aseffective Friedel Crafts alkylating agents in the presence of catalystssuch as antimony pentafluoride or phosphorus pentafluoride.

The process of the invention is of particular value in the fluorinationof steroids, especially since the configuration of the steroid isunaffected by the electrophilic fluorination reaction.

It is well known that introduction of a 9-fluorine atom into abiologically active steroids in many cases significantly enhances theactivity of the compound; the electrophilic fluorination process of theinvention provides a convenient route to a range of activefluorosteroids of this type. Thus, for example,3β,17β-di(trifluoroacetoxy)-5α-androstane may readily be converted toits 9α-fluoro anologue, which latter compound may subsequently beconverted by known methods to, for example, androgenically active9α-fluorosteroids such as9α-fluoro-11β,17β-dihydroxy-17α-methylandrost-4-en-3-one (Halotestin).

Introduction of a 9α-fluoro atom into an appropriately substitutedcorticosteroid, followed by dehydrofluorination to form a Δ⁹,11 -doublebond provides a convenient route to corticosteroids substituted at the9- and/or 11-positions and obviates the need to use, for example, ringC-oxygenated precursor starting materials such as hecogenin or to employa microbiological hydroxylation reaction to functionalise the11-position. 9,11-Dehydro steroids of use as intermediates in thesynthesis of 9- and/or 11-substituted anabolic steroids may similarly beprepared using this approach.

Alternatively, steroids carrying electron withdrawing substituents onthe A- or B-rings, for example the above-described compounds of formulaV, may be fluorinated in accordance with the invention to yield thecorresponding 14-fluorosteroid, which will exhibit physiologicalactivity of the same general type as the parent unfluorinated steroid,but usually at a modified level of activity. Such fluorosteroids, forexample the compounds of formulae VI, may readily be converted to the14-fluoro analogues of known biologically active, particularlyandrogenic and progestational, steroids.

Thus, for example,5α,6β-dibromo-14α-fluoro-3β-trifluoroacetoxyandrostan-17-one may beconverted to 14α-fluorotestosterone by a process involving debrominationto yield the corresponding Δ⁵,6 compound, reduction to yield3β,17β-dihydroxy-14α-fluoroandrost-5(6)-ene, and selective oxidation atthe 3-position (e.g. by Oppenauer oxidation following benzoylation ofthe 17-hydroxy group) to yield the 3-oxo-Δ⁴ -steroid. Similarly,deprotection of the 3-trifloroacetoxy group in the Δ⁵,6 compound andoxidation of the resulting hydroxy group (e.g. using Jones reagent)affords 14α-fluoroandrost-4-ene-3,17-dione; this last compound possessesvaluable anabolic activity, exhibiting an enhanced level of oralactivity compared to its 14α-hydrogen analogue.

5α,6β-Dibromo-14α-fluoro-3β-trifluoroacetoxypregnan-20-one may beconverted to 14α-fluoroprogesterone by debromination and reduction orhydrolysis to yield the corresponding 3-hydroxy-Δ⁵,6 -steroid, andoxidation to the desired 3-oxo-Δ⁴ -steroid; 14α-fluoroprogesteroneexhibits a higher level of progestational activity on oraladministration than does its 14α-hydrogen analogue. A range of14α-fluorocorticosteroids may be prepared by similar methods.

Similarly, appropriately substituted steroids having a hydrocarbon groupat the 17β-position may be converted in accordance with the invention totheir 17α-fluoro analogues. Thus, for example,5α,6β-dichloro-3β-trifluoroacetoxycholestane may be fluorinated at the17α-position and the resulting 17α-fluorosteroid may be converted to17α-fluorocholesterol by dechlorination and hydrolytic or hydrogenolyticcleavage of the trifluoroacetyl group at the 3-position.

14-Fluorosteroids, for example the 14-fluoro derivatives describedabove, are novel compounds, possessing useful biological activity ashereinbefore described or constituting intermediates for activecompounds, and comprise a further feature of the present invention.

Novel 14α-fluorosteroids embraced by the invention include compoundshaving the formula ##STR9## where R¹⁸ represents hydroxy or protectedhydroxy (e.g. esterified hydroxy such as acetoxy, trifluoroacetoxy ornitrooxy) and R¹⁹ represents hydrogen (α- or β), or R¹⁸ and R¹⁹ togetherrepresent a keto or protected keto (e.g. ketal) group, R²⁰ representshydrogen and R²¹ and R²² both represent hydrogen or halogen (e.g.chlorine or bromine) or together form a double bond or an epoxy group,and when R¹⁸ and R¹⁹ together represent a keto group, R²⁰ and R²¹ maytogether form a carbon-carbon double bond or an epoxy group, R²² thenbeing hydrogen, or R¹⁸ and R²¹ together form a 3,5-cyclo linkage, R¹⁹and R²⁰ then being hydrogen and R²² being hydroxy or protected hydroxy(e.g. esterified hydroxy such as acetoxy); R²³ represents hydrogen,methyl, hydroxy or protected hydroxy (α- or β-); R²⁴ representshydrogen, hydroxy or protected hydroxy (e.g. esterified hydroxy such asacetoxy) and R²⁵ represents acetyl or substituted acetyl (e.g.hydroxyacetyl or protected hydroxyacetyl, for example acyloxyacetyl suchas acetoxyacetyl), or R²⁴ represents hydrogen and R²⁵ represents hydroxyor protected hydroxy (e.g. esterified hydroxy such as acetoxy) or R²⁴and R²⁵ together represent a keto group.

Fluorinated steroids obtained in accordance with the invention may alsobe of value in the synthesis of various unsaturated steroids, since itis possible to promote elimination of the fluorine atom together with ahydrogen atom from an adjacent carbon atom so that a carbon-carbondouble bond is formed. The elimination may be promoted by acidcatalysis, suitable catalysts including hydrogen fluoride and Lewisacids such as boron trifluoride, conveniently employed in the form of anetherate. Dehydrofluorination of, for example, 14-fluorosteroidsobtained in accordance with the invention provides a convenient route toa range of Δ¹⁴ -steroids of value as intermediates in the synthesis ofmedically important cardenolides.

The following Examples serve to illustrate the invention. Alltemperatures are in ° C. Where bottles of fluorine are referred to,these contain an overall gas pressure of about 3 atmospheres.

EXAMPLE 1 Fluorination of Adamantane using Trifluoromethyl Hypofluorite

i. A solution of adamantane (250 mg, 1.84 mmole) influorotrichloromethane (30 ml) at -25° was treated with gaseoustrifluoromethyl hypofluorite (2 mmoles), air being admitted to thereaction vessel during the course of the gas addition.

After 30 minutes the reaction product was isolated by evaporation of thesolvent in vacuo and was shown by g.l.c. to contain 69% of1-fluoroadamantane, 4% of polyfluorinated adamantane derivatives and 27%of unreacted adamantane. The FMR spectrum of the product showed a singlepeak at φ* + 128 (s) ppm.

A repeat of the above procedure in which degassed fluorotrichloromethanewas employed as the solvent and air was excluded from the reactionsystem gave a product containing (as measured by g.l.c.) 46% of1-difluoroadamantane, 24% of polyfluorinated adamantane derivatives and30% of unreacted adamantane. The FMR spectrum of this product showedpeaks at φ* + 49 (s), 128 (s), 130 (s), 132 (s), 174 (m) and 182 (m)ppm, confirming that the absence of a free radical inhibitor such asoxygen led to the formation of a range of fluorinated by-products.

ii. A solution of adamantane (250 mg, 1.84 mmole) in degassedfluorotrichloromethane (30 ml) to which had been added benzoquinone (195mg, 1.84 mmole) was treated at -25° with trifluoromethyl hypofluorite (2mmoles).

After 30 minutes the fluorotrichloromethane was evaporated off in vacuo,the residue was added to hexane, and the resulting solution was filteredto remove benzoquinone and derivatives thereof. The reaction product wasshown by g.l.c. to contain 71% of 1-fluoroadamantane, 6.5% ofpolyfluorinated adamantanes and 22.5% of unreacted adamantane.

EXAMPLE 2 Fluorination of Adamantane using Molecular Fluorine

A solution of adamantane (272 mg, 2 mmole) in a mixture offluorotrichloromethane (200 ml) and ethanol-free chloroform (20 ml) wastreated at -75° with a slow stream of fluorine (6% v/v in nitrogen,total quantity of fluorine ca. 5 mmole) over a period of 4 hours, thefluorine/nitrogen gas mixture being introduced with vigorous stirringinto the reaction solution through a sintered glass disc. The solutionwas subsequently flushed well with nitrogen, washed successively withaqueous sodium bicarbonate and water and was then dried.

The reaction product was obtained by evaporation of the solvent in vacuoand was shown by g.l.c. (3% Hi-efficiency 6 foot coloumn, temperature135°, nitrogen flow rate 15 ml/min.) to consist of 75%1-fluoroadamantane, 9% more polar material (principally polyfluorinatedderivatives) and 16% unreacted adamantane.

The product was chromatographed on silica gel (75 g). Elution withhexane gave adamantane (40 mg) identical with an authentic sample (IRspectroscopy and g.l.c. retention time); elution with chloroform :hexane (1:9) gave 1-fluoroadamantane (232 mg) which was recrystallizedfrom hexane. This recrystallized product (219 mg, 83.5% based onrecovered starting material) had m.p. 261°-263° (sealed tube), a singleFMR peak at φ* + 128.5 (s) ppm, and IR spectrum identical with anauthentic sample.

EXAMPLE 3 Fluorination of 1-Trifluoroacetamidoadamantane usingTrifluoromethyl Hypofluorite

A solution of 1-trifluoroacetamidoadamantane (3 g, 12.1 mmole) influorotrichloromethane (40 ml), containing nitrobenzene (1.5 g, 12.2mmole), was treated with trifluoromethyl hypofluorite (13 mmole) at -25°for 17 hours, air being admitted to the reaction vessel during thistime. The solution was then purged with nitrogen to remove excesstrifluoromethyl hypofluorite and the solvent was removed in vacuo. Theresidue was dissolved in chloroform, washed with aqueous sodiumbicarbonate and water, and then dried, whereafter the product waschromatographed on silica gel (100 g). Elution with chloroform initiallyafforded unreacted starting material (70 mg), followed by3-fluoro-1-trifluoroacetamido adamantane (2.1 g), which appearedhomogeneous by g.l.c. After recrystallization from ether:hexane thisproduct exhibited m.p. 66.5°-68.5°.

EXAMPLE 4 Fluorination of 1-Trifluoroacetoxyadamantane usingTrifluoromethyl Hypofluorite

A solution of 1-trifluoroacetoxyadamantane (1.0 g, 4.0 mmole, preparedby reacting adamantan-1-ol with trifluoroacetic anhydride in drypyridine) in fluorotrichloromethane (10 ml), containing m-dinitrobenzene(80 mg, 0.48 mmole), was treated with trifluoromethyl hypofluorite (4.5mmole) at -25° for 24 hours, air being recrystallization admitted to thereaction vessel during this time. The product was recovered in a similarmanner to that described in Example 3 and was chromatographed on silica(100 g). Elution with chloroform:hexane (1:5) afforded unreactedstarting material (152 mg), while elution with chloroform:hexane (1:4)gave liquid 3-fluoro-1-trifluoroacetoxyadamantane (489 mg) whichappeared homogeneous by g.l.c. This product sublimed at 70° (bath)/1 mmHg to give a crystalline solid m.p. 28°-32°; ν_(max) (film) 1780 cm⁻ ¹ ;PMR 1.5-2.6 (m, adamantyl protons); FMR φ* + 76.2 (s, CF₃ COO--) and +133.5 (broad s) ppm.

Fluorination of 1-trifluoroacetoxyadamantane in chloroform at roomtemperature, using trifluoromethyl hypofluorite in the absence of airand free radical inhibitors such as m-nitrobenzene, gave a complexmixture of products showing a large number of peaks on g.l.c. analysis.The FMR spectrum of this product indicated the presence of severalmonofluoro derivatives and a mixture of polyfluorinated derivatives,indicating that the fluorination has proceeded principally by a freeradical mechansim.

EXAMPLE 5 Fluorination of Adamantan-1-ol using TrifluoromethylHypofluorite

A solution of adamantan-1-ol (0.75 g, 5 mmole) in 2,2,2-trifluoroethanol(10 ml), containing nitrobenzene (70 mg, 0.57 mmole), was treated withtrifluoromethyl hypofluorite (5.5 mmole) at -25° for 8 hours, whereafterthe reaction solution was purged with nitrogen and the product recoveredin a similar manner to that described in Example 3. Recrystallizationfrom ether:hexane gave a mixture of 3-fluoroadamantan-1-ol and3,5-difluoroadamantan-1-ol (ca. 6:1 by g.l.c. analysis and integrationof FMR peaks φ* + 133 (s) and + 139 (s) ppm) (0.52 g, ca 60%). The3-fluoroadamantan-1-ol component was isolated by p.l.c. (silica gel,eluting with chloroform:hexane) and was verified by microanalysis and bycomparison (IR, PMR, FMR) with 3-fluoroadamtan-1-ol obtained byhydrolysis (using methanolic sodium hydroxide at room temperature) of3-fluoro-1-trifluoroacetoxyadamantane prepared as in Example 4.

EXAMPLE 6 (i) Fluorination of 3β, 17β-Di(trifluoroacetoxy)-5α-androstane using Trifluoromethyl Hypofluorite

A well-stirred solution of 3β, 17β-di(trifluoroacetoxy)-5α-androstane(2.5 g, 5.15 mmole, prepared by treatment of 5α-androstane-3β,17β-diolwith trifluoroacetic anhydride in pyridine), nitrobenzene (800 mg, 6.5mmole) and sodium trifluoroacetate (10 g, 73.5 mmole) influorotrichloromethane (45 ml) was treated with trifluoromethylhypofluorite (8.5 mmole) at -20° for 2.5 hours, air being admitted tothe reaction vessel during this time. Thereafter the solution was purgedwith nitrogen and the solvent was removed in vacuo. The residue wasdissolved in chloroform and the resulting solution was washed withaqueous sodium bicarbonate and water and was then dried, whereafter theproduct was chromatographed on silica gel (125 g). Elution withchloroform:hexane (3:7) gave unreacted starting material (308 mg), whilesubsequent elution with chloroform:hexane (7:13) gave3β,17β-di(trifluoroacetoxy)-9α-fluoro-5α-androstane (1.02 g), whichcrystallized from hexane as prisms (917 mg) m.p. 140°-142°; [α] ₂₄^(D) - 22° (c 1.47, CHCl₃). (Found C,55.10; H,5.78; F,26.35%;m/e 502.C₃₃ H₂₉ O₄ F₇ requires C,54.97; H,5.82; F,26.47%; M⁺ 502).

(ii) 9α-Fluoro-5α-androstane-3,17-dione

The product of (i) above (260 mg) in a mixture of methanol (25 ml),tetrahydrofuran (12 ml) and 2N aqueous sodium hydroxide (10 ml) wasstirred at room temperature for 1 hour. Most of the solvent wasevaporated off in vacuo and the residue was diluted with water,whereafter 3β,17β-dihydroxy-9α-fluoro-5α-androstane hydrate (210 mg) wasrecovered by filtration. The product crystallised from chloroform:hexaneas prisms (179 mg) m.p. 195°-196°; [α]_(D) ²⁴ -10° (c 0.49, CHCl₃);ν_(max) 3550, 3400 and 3250 cm.sup.⁻¹ ; PMR spectrum includes signals atδ 0.75 (3H,s, 18-Me), 0.94 (3H,s, 19-Me) and 3.65 (2H, m, CH.OH); FMRφ* + 179.5 ppm (multiplet ca 80 Hz in width).

A sample of the 3,17-diol prepared as above (280 mg) in acetone (120 ml)at 0° was treated with an excess of Jones reagent (0.4 ml), using themethod of Djerassi et al; J. Org. Chem. 21, 1547 (1956), for 15 minutes.Excess Jones reagent was destroyed by the addition of isopropanol (0.5ml) and water (15 ml) was added. The organic solvents were thenevaporated off in vacuo and the aqueous residue was treated with etherto give the title compound (268 mg), which crystallised fromacetone:hexane as prisms (265 mg) m.p. 188°-189°; [α]_(D) ²⁴ +82° (c1.71, CHCl₃); ν_(max) 1740 and 1725 cm.sup.⁻¹ ; PMR spectrum includessignals at δ0.89 (3H,s, 18-Me) and 1.15 (3H,s, 19-Me); FMR φ * +179.25ppm (multiplet ca 80 Hz in width). (Found: C74.37; H,8.83; F,6.24. C₁₉H₂₇ O₂ F requires C,74.47; H,8.83; F,6.20%).

EXAMPLE 7 Fluorination of 3β,17β-Di(trifluoroacetoxy)-5α-androstaneusing Molecular fluorine

A solution of 3β,17β-di(trifluoroacetoxy)-5α-androstane (968 mg, 2mmole) in fluorotrichloromethane (300 ml) and chloroform (15 ml) wastreated at -75° with a slow stream of fluorine (6% v/v in nitrogen,total quantity of fluorine ca 6.5 mmole) over a period of 3 hours, thefluorine:nitrogen gas mixture being introduced with vigorous stirringthrough a sintered glass disc. Thereafter the solution was purged withnitrogen and worked up in a similar manner to that described in Example6(i), the recovered product being chromatographed on silica gel (125 g).Elution with chloroform:hexane (1:2) afforded a semi-crystalline solid(248 mg) comprising unreacted starting material together with3β,17β-di(trifluoroacetoxy)-5α-androst-9(11)-ene. Further elution withchloroform-hexane (2:3) gave3β,17β-di(trifluoroacetoxy)-9α-fluoro-5α-androstane, which was shown byg.l.c. to be 95% pure. The product crystallised from hexane as prisms(347 mg) m.p. 140°-142° and was found to identical (IR, PMR and g.l.c.retention time) to the product of Example 6(i).

EXAMPLE 8 i. Fluorination of5α,6β-Dibromo-3β-trifluoroacetoxy-androstan-17 -one usingTrifluoromethyl Hypofluorite

A solution of 5α, 6β-dibromo-3β-trifluoroacetoxy androstan-17-one (550mg, 1 mmole, prepared from Δ⁵,6 -dehydroisoandrosterone bytrifluoroacetylation using trifluoracetic anhydride in pyridine andbromination using dioxan dibromide in chloroform carbon tetrachloride),nitrobenzene (360 mg, 2.9 mmole) and sodium trifluoroacetate (3.5 g,25.7 mmole) in fluorotrichloromethane (45 ml) was treated withtrifluoromethyl hypofluorite (3 mmole) for 6 hours at 0° and for afurther 9 hours at room temperature. The solution was then purged withnitrogen and worked up in a similar manner to that described in Example6(i) to yield a gum comprising crude5α,6β-dibromo-14α-fluoro-3β-trifluoroacetoxy androstan-17-one (545 mg),the PMR spectrum of which included signals at δ 1.05 (3H, s, 18-Me) and1.58 (3H, s, 19-Me).

The crude product, in ether (40 ml) and ethanol (40 ml), was treatedwith zinc dust (400 mg) and ammonium acetate for 17 hours at roomtemperature, whereafter the solution was filtered and the solventsremoved in vacuo. The product was dissolved in ether and chromatographedby p.l.c. (silica gel). Elution with ethyl acetate: hexane (1 : 1) (×2)and recovery of the major band gave14α-fluoro-3β-hydroxyandrost-5(6)-en-17-one (165 mg), which crystallisedfrom acetone: hexane as prisms (144 mg) m.p. 160°-161°; [α]_(D) ²⁴ +2.5° (c 0.75, CHCl₃); ν_(max) 3540 and 1745cm.sup.⁻¹ ; the PMR spectrumincluded signals at δ1.02 (6H, s, 18-Me and 19-Me), 3.5 (1H,m,3-CH.OH)and 5.42 (1H,m,6-CH); FMR φ * + 163.5 ppm (multiplet ca 80Hz wide).(Found: C, 74.27; H, 9.01; F, 6.04%; m/e 306. C₁₉ H₂₇ O₂ F requires C,74.47; H, 8.88; F, 6.20%; M⁺³⁰⁶).

ii. 14α-Fluoro-5α-androstane-3,17-dione

14α-Fluoro-3β-hydroxyandrost-5(6)-en-17-one (400mg) in ethanol (70 ml)was hydrogenated over palladium-charcoal (5%; 250 mg) until uptake ofhydrogen ceased (72 hr). The solvent was evaporated in vacuo and thecrude product was recrystallised from acetone: hexane to give prisms of

14α-fluoro-3β-hydroxy-5α-androstan-17-one (158 mg) m.p. 201°-202°;[α]_(D) ²³ + 83° (c 0.84, CHCl₃); ν_(max) 3500 and 1730 cm.sup.⁻¹ ; thePMR spectrum included signals at δ 0.83 (3H, s, 19-Me), 1.00 (3H, s,18-Me) and 3.6 (1H, m, 3-CHOH); FMR φ * + 164 ppm (broad multiplet ca 80Hz wide).

The hydrogenated product (122 mg) in acetone (30 ml) at 0° was treatedwith an excess of Jones reagent (0.15 ml) for 15 min., whereafterisopropanol was added and the product recovered in a similar manner tothat described in Example 6 (ii). Recrystallisation from acetone: hexaneafforded needles of the title compound (106 mg) m.p. 181°-182°; [α]_(D)²³ + 105.5° (c 0.63, CHCl₃); ν_(max) 1725 and 1755 cm.sup.⁻¹ ; the PMRspectrum included a signal at δ 1.03 (6H, s, 18-Me) and 19-Me); FMR100 * + 163.8 ppm (broad multiplet ca 80 Hz wide).

iii. 3β-Hydroxyandrost-5(6), 14-dien-17-one

A solution of 14α-fluoro-3β-hydroxyandrost-5(6)-en-17-one (200 mg),prepared as described in (i) above, in pyridine (20 ml) was treated withtrifluoracetic anhydride (140 mg) at 0° for 10 minutes to give14α-fluoro-3β-trifluoroacetoxyandrost-5(6)-en-17-one which was isolatedand recrystallised from acetone: hexane as prisms (209 mg) m.p.175°-176°; [α]_(D) ²⁵ - 12.5° (c 4.1, CHCl₃).

This trifluoroacetate (200 mg) in dry benzene (50 ml) was treated withboron trifluoride-etherate (150 mg) at room temperature for 10 min.Water (25 ml) was added, and the organic layer was separated and washedwith sodium bicarbonate and water, and was then dried. Removal of thesolvent in vacuo gave a gum which was chromatographed on Keisel gel GF254 (150 g) eluting with ethyl acetate: hexane (1:9). The earlyfractions, which were shown by t.l.c. [ethyl acetate: hexane (1:9)] tocontain a single spot (Rf 0.65), were combined to give3-trifluoroacetoxyandrost-5(6), 14-dien-17-one (38 mg), whichcrystallised from acetone: hexane as prisms (32 mg) m.p. 160°-162°;[α]_(D) ²³ + 46° (c 0.75, CHCl₃). Further elution of the column gavefractions shown by t.l.c. to contain a single spot (Rf 0.5); these werecombined to give 3-trifluoroacetoxyandrost-5(6), 8 (9)-dien-17-one (52mg), the thermodynamic product of the elimination. This productcrystallised from methanol (at -20°) as plates (15 mg) m.p. 109°-115°.

3-Trifluoroacetoxyandrost-5(6),14-dien-17-one (15 mg) in tetrahydrofuran(3 ml) and methanol (2 ml) was treated with 2N aqueous sodium hydroxide(1 ml) at 0° for 3 min. The solution was diluted with water (15 ml), theorganic solvents were evaporated off in vacuo, and the residue wasextracted with ether to give the title compound (11 mg), whichcrystallized from acetone-hexane as prisms (8 mg), m.p. 161°-164°,identical [IR and t.l.c. (ethyl acetate-hexane 1:3)] with an authenticsample. Two recrystallizations raised the m.p. to 165°-168°.

iv. 14α-Fluoroandrost-4-ene-3, 17-dione

A solution of 14α-fluoro -3β-hydroxyandrost-5(6)-en-17 -one (93 mg),prepared as described in (i) above, in acetone (20 ml) was treated withJones reagent (0.10 ml) at 0°-5° for 5 min. Excess Jones reagent wasdestroyed by the addition of isopropanol (0.2 ml) and water (5 ml) wasadded. The organic solvents were then evaporated off in vacuo and theaqueous residue was extracted with chloroform. The chloroform wasevaporated in vacuo and the thus-obtained residue dissolved in warmmethanol (10 ml). The resulting solution was treated with one drop of 2Naqueous sodium hydroxide and warmed on a steam bath for 5 min. Theorange solution so obtained was neutralized with acetic acid, water wasadded, and the organic solvents were evaporated of in vacuo. The residuewas extracted with chloroform, and the solution was washed with sodiumbicarbonate and water, and then dried. Evaporation of the chloroform invacuo gave a solid (92 mg) which was chromatographed by p.l.c. (silicagel) eluting with ethyl acetate: hexane (1:1). Recovery of the majorband gave the title compound (68 mg), which crystallised from acetone asprisms (58 mg) m.p. 216°-217°; [α]_(D) ²⁴ + 181° (c 0.69, CHCl₃); λmax(ethanol) 239 nm (ε 12,900); ν_(max) 1740, 1660 and 1615 cm.sup.⁻¹ ; thePMR spectrum included signals at δ1.05 (3H, s, 18-Me), 1.22 (3H,s,19-Me) and 5.8 (1H, s, 4-H); FMR φ* + 164.5 ppm (broad multiplet ca 90Hz wide). (Found: C, 74.82; H, 8.23; F, 6.30, C₁₉ H₂₅ O₂ F requiresC,74.97; H,8.28; F,6.24%).

EXAMPLE 9 i. Fluorination at5α,6β-Dibromo-3β-trifluoroacetoxypregnan-20-one using TrifluoromethylHypofluorite

a. Preparation of starting material

Pregnenolone (10 g, 31.5 mmole) in pyridine (100 ml) was treated withtrifluoroacetic anhydride (7.5 g) at room temperature for 15 minutes togive 3β-trifluoroacetoxy pregn-5(6)-en-20-one, which was isolated as anethyl acetate solution and recrystallised from acetone as prisms (10.36g) m.p. 155°-156°; [α]_(D) ²⁵ + 4.5° (c 1.63, CHCl₃).

The thus-obtained trifluoroacetate (4.125g, 10 mmole) in chloroform (20ml) and carbon tetrachloride (40 ml) was treated with dioxan dibromide(5g, 20 mmole) and the solution was stirred with potassium carbonate (10g) at room temperature in the dark, for 16 hours. Excess bromine wasremoved in vacuo, and the solution was filtered, washed with water anddried. Evaporation of the solvent afforded5α,6β-dibromo-3β-trifluoroacetoxypregnan-20-one, which wasrecrystallised from ether: hexane (yield 4.02 g) m.p. 142°-145°; [α]_(D)²³ -15.5° (c 0.98, CHCl₃).

b. Fluorination

The 5α,6β-dibromo compound prepared in (a) above (1.145 g, 2 mmole),nitrobenzene (375 mg, 3 mmole) and sodium trifluoroacetate (4g, 29.5mmole) were dissolved in fluorotrichloromethane (125 ml) and treatedwith trifluoromethyl hypofluorite (3 mmole) at -15° to -20° for 7 hours,air being admitted to the reaction vessel during this time. The solutionwas then purged with nitrogen and worked up in a similar manner to thatdescribed in Example 6 (i) to yield a gum comprising crude5α,6β-dibromo-14α-fluoro-3β-trifluroacetoxypregnan-20-one, which wasimmediately treated with zinc dust (800 mg) and ammonium acetate (1.6g)in ether (80 ml) and ethanol (80 ml) for 24 hours at room temperature,whereafter the solution was filtered and the solvents removed in vacuo.The product was dissolved in ether and immediately chromatographed on aKieselgel GF 254 column (150 g) eluting with ethyl acetate: hexane (2 :3). Early fractions afforded pregnenolone (166 mg) while later fractionsgave 14α-fluoropregnenolone (291 mg), which crystallised from acetone :hexane as prisms (256 mg) m.p. 198°-202° (dec); [α]_(D) ²³ + 32.5° (c0.65, CHCl₃); max 3600 and 1695 cm.sup.⁻¹ ; the PMR spectrum includedsignals at δ 0.77 (3H, s, 18-Me), 1.00 (3H, s, 19-Me), 2.12 (3H, s,21-Me), 3.0 (m, 17-H), 3.5 (m, 3-H) and 5.4 (1H, m, 6-H); FMR φ* + 164ppm (broad multiplet ca 90-100 Hz wide). (Found: C, 75:52; H, 9.25%; m/e334. C₂₁ H₃₁ O₂ F requires C, 75.41; H 9.34; F, 5.68%; M+ 334).

ii. 14α-Fluoropregn-4-ene-3,20-dione(14α-Fluoroprogesterone)

The product of (i)(b) above (80 mg) in acetone (75 ml) at 0° was treatedwith Jones reagent (0.10 ml) for 5 min. The solution was then worked upas described in Example 8 (iv) and the thus-obtained crystalline productwas chromotographed by p.l.c. (silica gel) eluting with ethylacetate:hexane(2:3). Recovery of the major band gave the title compound(61 mg) which crystallized from acetone-hexane as prisms (57 mg) m.p.175°-175.5°; [α]_(D) ²³ +204° (c 1.0, CHCl₃); ν_(max) 1695, 1665 and1620 cm.sup.⁻¹ ; λ_(max). (ethanol) 239 nm (ε, 12,000); the PMR spectrumincluded signals at δ0.73 (3H, s, 18-Me), 1.17 (3H, s, 19-Me), 2.11 (3H,s, 21-Me) and 5.8 (s, 4-H); FMR φ* 164 ppm.

EXAMPLE 10 Fluorination of 5α,6β-Dichloro-3α-trifluoroacetoxycholestaneusing Trifluoromethyl Hypofluorite

5α,6β-DIchloro-3β-trifluoroacetoxycholestane dissolved influorotrichloromethane was reacted with trifluoromethyl hypofluorite inthe presence of nitrobenzene and sodium trifluoroacetate in analogousmanner to the process of Example 9 (i) (b). The product was treated withzine dust and ammonium acetate in ether and ethanol and worked up usdescribed in Example 9 (i) (b) to yield, after chromatography,17α-fluorocholesterol m.p. 149°. (Found C, 80.23; H, 11.51; F, 4.15%.C₂₇ H₄₅ OF requires C, 80.20; H, 11.14; F 4.70%).

EXAMPLE 11 Fluorination of3β-Acetoxy-17α-hydroxy-16β-methyl-5α-pregnan-20-one using MolecularFluorine

3β-Acetoxy-17α-hydroxy-16β-methyl-5α-pregnan-20-one (1g, prepared bytreatment of the corresponding 3β-ol with acetic anhydride in pyridine)was dissolved in fluorotrichloromethane (250 ml) and chloroform (200 ml)containing sodium trifluoroacetate (ca. 2g) and sodium fluoride (ca.2g). The resulting solution was cooled to -78° and vigourously stirred,whereupon fluorine from four 750 cc bottles (8-10% v/v fluorine innitrogen) was added over 9-10 hours. The reaction solution was thenpoured into aqueous sodium thiosulphate and the organic layer wasseparated, washed with water, dried over potassium carbonate andevaporated to dryness. The residue was purified by liquidchromatography, eluting with cyclohexane containing 30% v/v ethylacetate and 0.1% v/v pyridine, to yield3β-acetoxy-9α-fluoro-17α-hydroxy-16β-methyl-5α-pregnan-20-one (50%);m.p. 150° (after recrystallisation from acetone); PMR spectrum includessignals at δ 2.20 (21-Me), 2.00 (3-0.CO.CH₃), 0.92 (19-Me) and 0.87(18-Me); FMR φ* + 179.5 ppm. (Found: C, 70.51; H, 9.20; F, 4.48; C₂₄ H₃₇FO₄ requires C, 70.55; H, 9.13; F, 4.65%).

EXAMPLE 12 Fluorination of21-Acetoxy-17α-hydroxy-16β-methyl-5α-pregnane-3,20-dione using MolecularFluorine

21-Acetoxy-17α-hydroxy-16β-methyl-5α-pregnane-3,20-dione (1.3g, preparedby oxidation of the corresponding 3β-ol with aqueous sodiumdichromate/sulphuric acid/acetic acid) was dissolved influorotrichloromethane (250 ml) and chloroform (200 ml) containingsodium trifluoroacetate (ca. 2g) and sodium fluoride (ca. 2g). Theresulting solution was cooled to -78° and vigorously stirred, whereuponfluorine from four 750 cc bottles (9-10% v/v fluorine in nitrogen) wasslowly bubbled through the solution. The reaction solution was thenpoured into aqueous sodium thiosulphate and the organic layer wasseparated, washed with water, dried over potassium carbonate andevaporated to dryness. The residue was purified by liquidchromatography, eluting with methylene chloride containing 15% v/v ethylacetate and 0.1% v/v pyridine, and two fractions were collected. Theless polar fraction was 21-acetoxy-14α-fluoro-17α-hydroxy-16β-methyl-5α-pregnane-3,20-dione (20%); m.p. 125° (after recrystallisation fromacetone); PMR spectrum includes signals at δ 4.91 (2H, --CH₂ OAc), 2.17(21 -- O. CO.CH₃), 1.03 (19-Me) and 0.90 (18-Me); FMR φ* + 160 ppm (J^(w) /2 = 80 Hz). (Found: C, 65.56; H, 8.71; F, 3.93; C₂₄ H₃₅ FO₅requires C, 65.43; H, 8.47; F, 4.31%). The more polar fraction was21-acetoxy-9α-fluoro-17α-hydroxy-16β-methyl-5α-pregnane-3,20-dione(31%); m.p. 163° (after recrystallisation from acetone); PMR spectrumincludes signals at δ 4.97 (2H, --CH₂ OAc), 2.18 (21-O. CO.CH₃), 1.12(19-Me) and 0.83 (18-Me); FMR φ* + 179 ppm (J ^(w) /2 = ca. 80 Hz).(Found: C, 66.88; H, 8.79; F, 4.21; C₂₄ H₃₅ FO₅. 1/2 H₂ O requires C,66.80; H, 8.47; F, 4.40%).

EXAMPLE 13 i. Fluorination of 3β-Acetoxy-5α,6β-dichloropregnan-20-oneusing Molecular Fluorine

a. Preparation of starting material

A solution of pregnenolone acetate (10g) in dry benzene was added inportions to a stirred solution of chlorine in benzene (60ml) andpyridine (0.5ml) until the yellow colour of the chlorine solutiondisappeared. Further chlorine was then added, followed by furtherportions of ths steroid solution until the yellow colour againdisappeared. This procedure was continued until all the steroid solutionhad been added and a permanent light yellow colour remained. Thesolution was stirred for a further 5 minutes and then poured intoaqueous sodium thiosulphate. The organic layer was separated, washedwith water, dried over potassium carbonate and evaporated to dryness.The residue was crystallised from acetone to give3β-acetoxy-5α,6β-dichloropregnan-20-one (85%); m.p. 187°.

b. Fluorination

3β-Acetoxy-5α,6β-dichloropregnan-20-one (1.4g) was dissolved influorotrichloromethane (250 ml) and chloroform (200 ml) containingsodium trifluoroacetate (ca. 2g) and sodium fluoride (ca. 2g). Theresulting solution was cooled to -78° and vigourously stirred, whereuponfluorine from four 750 cc bottles (10% v/v fluorine in nitrogen) wasbubbled through the solution over a period of 8 hours. The reactionsolution was then poured into aqueous sodium thiosulphate and theorganic layer was separated, washed with water, dried over potassiumcarbonate and evaporated to dryness to yield crude3β-acetoxy-5α,6β-dichloro-14α-fluoropregnan-20-one.

The crude product was dissolved in ethanol containing zinc and ammoniumacetate and refluxed for 3 hours. The resulting mixture was filtered andthe filtrate was evaporated to dryness in vacuo. Water and chloroformwere added to the solid residue, whereafter the organic layer wasseparated, washed with water, dried and evaporated. A portion of thesolid residue so obtained was purified by liquid chromatography, elutingwith cyclohexane containing 17% v/v ethyl acetate and 0.1% v/v pyridine,to yield 3β-acetoxy-14α-fluoropregn-5(6)-en-20-one (400 mg, 65%); m.p.128° (after recrystallisation from methanol); PMR spectrum includessignals at δ 5.30 (1H, m, 6-H), 4.50 (1H, m, 3α-H), 2.10 (21-Me), 2.00(3--0.CO.CH₃), 1.00 (19-Me) and 0.75 (18-Me); FMR φ* 162 ppm (J ^(w) /2= ca. 80 Hz). (Found: C, 73.59; H, 8.96; F, 4.89; C₂₃ H₃₃ FO₃ requiresC, 73.37; H, 8.83; F, 5.04%).

ii. 3β-Acetoxypregna-5(6), 14-dien-20-one

The remainder of the crude product from (i) (b) above was dissolved inethylene glycol (30 ml) containing pulverised sodium hydroxide (0.5g),and the resulting solution was stirred overnight under nitrogen at70°-80°. The reaction solution was then poured into water, the resultingmixture was extracted with chloroform, and the chloroform layer waswashed with water and evaporated. The oily residue was chromatographedon silica gel and eluted with hexane containing 30% v/v ethyl acetate togive the title compound which was recrystallised from methanol (220 mg,45% overall); m.p. 205°-8°; PMR spectrum includes signals at δ 5.33 (1H,m, 6-H), 5.10 (1H, m, 15-H), 3.53 (1H, m, 3α-H), 2.13 (21-Me), 1.00(19-Me) and 0.87 (18-Me).

EXAMPLE 14 Fluorination of 6β-Acetoxy-3α,5α-cyclopregnan-20-one usingMolecular Fluorine

a. Preparation of starting material

Pregnenolone p-toluenesulphonate (8g, prepared by reaction of pregnolonewith p-toluenesulphonyl chloride in pyridine) and potassium acetate(10g) were refluxed in a 1:1 mixture of acetone and water (300 ml) for36 hours. The reaction mixture was then poured into water (1 liter) andthe resulting mixture was extracted with chloroform. The chloroformlayer was then washed with water, dried and evaporated, and the residuewas recrystallised from acetone to give6β-hydroxy-3α,5α-cyclopregnan-20-one; m.p. 176°.

A solution of this product in pyridine (80ml) and acetic anhydride (70ml) was heated to 80° for 1 hour and was then stirred overnight. Theresulting solution was poured into water and the mixture so obtained wasextracted with chloroform. The chloroform layer was washed with water,dried and evaporated to give 6β-acetoxy-3α,5α-cyclopregnan-20-one (ca.30% from pregnenolone); PMR spectrum includes signals at δ4.47 (1H, t,J=3Hz, 6α-H), 2.1 (21-Me), 2.03 (6β-O.CO.CH₃), 1.0 (19-Me) and 0.7(18-Me).

b. Fluorination

6β-Acetoxy-3α,5α-cyclopregnan-20-one (1.5g) was dissolved influorotrichloromethane (250 ml) and chloroform (200 ml) containingsodium trifluoracetate (ca. 2g) and sodium fluoride (ca. 2g). Theresulting solution was cooled to -78° and vigourously stirred, whereuponfluorine from four bottles (each containing 12 mmoles at 0.5 Kg/cm²diluted to 3.5 Kg/cm² with nitrogen) was passed through. The reactionsolution was then poured into aqueous sodium thiosulphate and theorganic layer was separated, washed with water, dried over potassiumcarbonate and evaporated to dryness. The residue was purified by liquidchromatography, eluting with cyclohexane containing 17% v/v ethylacetate and 0.1% v/v pyridine, to give6β-acetoxy-14α-fluoro-3α,5α-cyclopregnan-20-one, which wasrecrystallised from methanol in 37% yield; m.p. 104°; PMR spectrumincludes signals at δ 4.56 (t, J=3 Hz, 6α-H), 2.1 (21-Me), 2.03 (6β-O.CO.CH₃), 1.0 (19-Me) and 0.82 (18-Me); FMR φ* + 162 ppm (J ^(w) /2 =80-90 Hz). (Found: C, 73.12; H, 8.88; F, 5.48; C₂₃ H₃₃ FO₂ requires C,73.37; H, 8.83; F, 5.04%).

EXAMPLE 15 Fluorination of 6β-Acetoxy-3α,5α-cycloandrostan-17-one usingMolecular Fluorine

6β-Acetoxy-3α,5α-cycloandrostan-17-one 1.5g, prepared from3β-hydroxyandrost-5-en-17-one using the method of Example 14a) wasdissolved in fluorotrichloromethane (250 ml) and chloroform (200 ml)containing sodium trifluoroacetate (ca. 2g) and sodium fluoride (ca.2g). The resulting solution was cooled to -78° and vigourously stirred,whereupon fluorine from four bottles (each containing 14 mmoles, ca. 10%v/v in nitrogen) was passed through. The reaction solution was thenpoured into aqueous sodium thiosulphate and the organic layer wasseparated, washed with water, dried over potassium carbonate andevaporated to dryness. The residue was purified by liquidchromatography, eluting with cyclohexane containing 25% ethyl acetateand 0.1% v/v pyridine, and three fractions were collected. The leastpolar component was unreacted starting material (400 mg). The nextfraction was 6β-acetoxy-9α-fluoro-3α,5α-cycloandrostan-17-one (27%corrected for recovered starting material); m.p. 110° (afterrecrystallisation from methanol); PMR spectrum includes signals at δ4.57 (t, J= 3 Hz, 6α-H), 2.06 (6β-O. CO.CH₃), 1.12 (19-Me) and 0.93(18-Me); FMR φ* + 179 ppm (broad signal, J^(w) /2 = 80 Hz). (Found: C,72.34; H, 8.53; F, 6.02; C₂₁ H₂₉ FO₃ requires C, 72.38; H, 8.39; F,5.45%). The most polar fraction was6β-acetoxy-14α-fluoro-3α,5α-cycloandrostan-17-one (20% corrected forrecovered starting material); m.p. 118° (after recrystallisation frommethanol); PMR spectrum includes signals at δ 4.63 (t, J=3 Hz, 6α-H),2.06 (6β-O. CO.CH₃), 1.07 (19-Me) and 1.06 (18-Me); FMR φ* + 163 ppm(broad signal, J ^(w) /2 = 80 Hz). (Found: C, 72.53; H, 8.61; F, 5.60;C₂₁ H₂₉ FO₃ requires C, 72.38; H, 8.39; F, 5.45%).

EXAMPLE 16 Fluorination of 3β,21-Diacetoxy-16β-methyl-17α-nitrooxy5α-pregnan-20-one using Molecular Fluorine

3β,21-Diacetoxy-16β-methyl-17α-nitrooxy-5α-pregnan-20 -one (1.5g,prepared by treating the corresponding 17α-ol with fuming nitric acid inacetic acid/acetic anhydride) was dissolved in a mixture of chloroform(200 ml) and fluorotrichloromethane (250 ml) containing sodium fluoride(ca. 2g) and sodium trifluoroacetate (ca. 2g). The resulting solutionwas then cooled to -75° C, vigourously stirred, and treated withfluorine (four 750 cc bottles each containing 0.5 Kg/cm² fluorinediluted to 3.5 Kg/cm² with nitrogen). The resulting reaction mixture waspoured into aqueous sodium thiosulphate, and the organic phase wasseparated, washed twice with water, treated with 2-3 drops of pyridine,and dried over magnesium sulphate. The organic solvents were thenevaporated to yield crude3β,21-diacetoxy-9α-fluoro-16β-methyl-17α-nitrooxy-5.alpha.-pregnan-20-oneas a white solid. A sample recrystallised from methanol exhibited thespectral characteristics ν_(max) 1750 (wide band, three carbonylabsorptions) and 1650 cm⁻ ¹ (17α-nitrate); PMR spectrum includes signalsat 4.66 (centre of ABq, J=16 Hz, 21-CH₂ OAc, together with 3α-Hresonance), 2.17 (s, C-21 acetoxy), 2.00 (s, 3-acetoxy), 0.9 and 0.77(C-18 and C-19 methyl); FMR φ* 179 (broad, J ˜ 80 Hz).

We claim:
 1. A process for the 9α-electrophilic fluorination of a saturated steroid compound containing a hydrogen atom bound to a tertiary carbon atom, wherein said steroid has a formula: ##STR10## where R⁴ represents protected hydroxy and R⁵ represents hydrogen, or R⁴ and R⁵ together represent a keto or protected keto group, and R⁶ and R⁷ each represent hydrogen, or R⁴ and R⁶ together represent a 3,5-cyclo linkage, R⁵ represents hydrogen and R⁷ represents protected hydroxy; R⁸ represents hydrogen, methyl or protected hydroxy; R⁹ represents hydrogen, hydroxy or protected hydroxy and R¹⁰ represents acetyl or substituted acetyl, or R⁹ represents hydrogen and R¹⁰ represents protected hydroxy, or R⁹ and R¹⁰ together represent a keto group; which comprises reacting the said steriod with an electrophilic fluorinating agent selected from the group consisting of molecular fluorine, pentafluorosulphur hypofluorite and lower fluoroalkyl hypofluorites in which the fluoroalkyl moiety contains at least two fluorine atoms per carbon atom, said fluorinating agent being substantially homogeneously dispersed in a liquid medium and said reaction being conducted in the presence of a free radical inhibitor to suppress formation of free fluorine radicals so that said hydrogen atom is electrophilically replaced by a fluorine atom, and recovering the thus-obtained fluoro steroid.
 2. A process as claimed in claim 1 wherein the electrophilic fluorinating agent is selected from the group consisting of molecular fluorine diluted with nitrogen and trifluoromethyl hypofluorite.
 3. A process as claimed in claim 1 wherein the free radical inhibitor is selected from the group consisting of oxygen, nitrobenzene, m-dinitrobenzene and benzoquinone.
 4. A process as claimed in claim 1 wherein chloroform, methylene chloride or tetrahydrofuran is employed as a free radical inhibitor and the electrophilic fluorinating agent is molecular fluorine diluted with nitrogen.
 5. A process as claimed in claim 1 wherein the fluorination is carried out in the presence of a substance which binds or adsorbs hydrogen fluoride.
 6. A process as claimed in claim 1 wherein, after the fluorination, a base is added to the crude fluoro steroid product in order to stabilize the said product.
 7. A process as claimed in claim 1 wherein R⁴ represents acetoxy, trifluoroacetoxy or nitrooxy and R⁵ represents hydrogen, or R⁴ and R⁵ together represent a keto group, and R⁶ and R⁷ each represent hydrogen, or R⁴ and R⁶ form a 3,5-cyclo linkage, R⁵ represents hydrogen and R⁷ represents acetoxy; R⁸ represents hydrogen or methyl; R⁹ represents hydrogen, hydroxy or nitrooxy and R¹⁰ represents acetyl or acetoxyacetyl, or R⁹ represents hydrogen and R¹⁰ represents acetoxy or trifluoroacetoxy.
 8. A process for the 14α-electrophilic fluorination of a saturated steroid compound containing a hydrogen atom bound to a tertiary carbon atom, wherein said steroid has a formula: ##STR11## where R¹¹ represents protected hydroxy and R¹² represents hydrogen, or R¹¹ and R¹² together represent a keto or protected keto group, R¹³ represents hydrogen and R¹⁴ and R¹⁵ each represent halogen, or R¹⁴ together with R¹³ or R¹⁵ represents an epoxy group, the remaining R¹³ or R¹⁵ representing hydrogen, or R¹¹ and R¹⁴ together represent a 3,5-cyclo linkage, R¹² and R¹³ each represent hydrogen and R¹⁵ represents protected hydroxy; and R¹⁶ represents oxo, acetyl or protected hydroxy; which comprises reacting the said steroid with an electrophilic fluorinating agent selected from the group consisting of molecular fluorine, pentafluorosulphur hypofluorite and lower fluoroalkyl hypofluorites in which the fluoroalkyl moiety contains at least two fluorine atoms per carbon atom, said fluorinating agent being substantially homogeneously dispersed in a liquid medium and said reaction being conducted in the presence of a free radical inhibitor to suppress formation of free fluorine radicals so that said hydrogen atom is electrophilically replaced by a fluorine atom, and recovering the thus-obtained fluoro steroid.
 9. A process as claimed in claim 8 wherein the electrophilic fluorinating agent is selected from the group consisting of molecular fluorine diluted with nitrogen and trifluoromethyl hypofluorite.
 10. A process as claimed in claim 8 wherein the free radical inhibitor is selected from the group consisting of oxygen, nitrobenzene, m-dinitrobenzene and benzoquinone.
 11. A process as claimed in claim 8 wherein chloroform, methylene chloride or tetrahydrofuran is employed as a free radical inhibitor and the electrophilic fluorinating agent is molecular fluorine diluted with nitrogen.
 12. A process as claimed in claim 8 wherein the fluorination is carried out in the presence of a substance which binds or adsorbs hydrogen fluoride.
 13. A process as claimed in claim 8 wherein, after the fluorination, a base is added to the crude fluoro steroid product in order to stabilize the said product.
 14. A process as claimed in claim 8 wherein R¹¹ represents acetoxy, trifluoroacetoxy or nitrooxy and R¹² represents hydrogen, or R¹¹ and R¹² together represent a keto group, R¹³ represents hydrogen and R¹⁴ and R¹⁵ each represent chloro or bromo, or R¹¹ and R¹⁴ form a 3,5-cyclo linkage, R¹² and R¹³ each represent hydrogen and R¹⁵ represents acetoxy; and R¹⁶ represents oxo, acetyl or acetoxy.
 15. A process for the 17α-electrophilic fluorination of a saturated steroid compound containing a hydrogen atom bound to a tertiary carbon atom, wherein said steriod has a formula: ##STR12## wherein R¹¹ represents protected hydroxy and R¹² represents hydrogen, or R¹¹ and R¹² together represent a keto or protected keto group, R¹³ represents hydrogen and R¹⁴ and R¹⁵ each represent halogen, or R¹⁴ together with R¹³ or R¹⁵ represents an epoxy group, the remaining R¹³ or R¹⁵ representing hydrogen, or R¹¹ and R¹⁴ together represent a 3,5-cyclo linkage, R¹² and R¹³ each represent hydrogen and R¹⁵ represents protected hydroxy; and R¹⁷ represents a C₂₋₁₂ saturated hydrocarbyl group which comprises reacting the said steriod with an electrophilic fluorinating agent selected from the group consisting of molecular fluorine, pentafluorosulphur hypofluorite and lower fluoroalkyl hypofluorites in which the fluoroalkyl moiety contains at least two fluorine atoms per carbon atom, said fluorinating agent being substantially homogeneously dispersed in a liquid medium and said reaction being conducted in the presence of a free radical inhibitor to suppress formation of free fluorine radicals so that said hydrogen atom is electrophilically replaced by a fluorine atom, and recovering the thus-obtained fluoro steroid.
 16. A process as claimed in claim 15 wherein the electrophilic fluorinating agent is selected from the group consisting of molecular fluorine diluted with nitrogen and trifluoromethyl hypofluorite.
 17. A process as claimed in claim 15 wherein the free radical inhibitor is selected from the group consisting of oxygen, nitrobenzene, m-dinitrobenzene and benzoquinone.
 18. A process as claimed in claim 15 wherein chloroform, methylene chloride or tetrahydrofuran is employed as a free radical inhibitor and the electrophilic fluorinating agent is molecular fluorine diluted with nitrogen.
 19. A process as claimed in claim 15 wherein the fluorination is carried out in the presence of a substance which binds or adsorbs hydrogen fluoride.
 20. A process as claimed in claim 15 wherein, after the fluorination, a base is added to the crude fluoro steroid product in order to stabilize the said product.
 21. A process as claimed in claim 15 wherein R¹¹ represents nitrooxy or trifluoroacetoxy; R¹² and R¹³ each represent hydrogen; R¹⁴ and R¹⁵ both represent chloro or bromo or together form an epoxy group; and R¹⁷ represents the group --CH(CH₃) . (CH₂)₃.CH(CH₃)₂.
 22. A compound having the formula: ##STR13## wherein R¹⁸ represents hydroxy, nitroxy, acetoxy or trifluoroacetoxy and R¹⁹ represents hydrogen or R¹⁸ and R¹⁹ together represent a keto group, R²⁰ represents hydrogen and R²¹ and R²² both represent hydrogen, chlorine or bromine or together form a carbon-carbon double bond or an epoxy group, and when R¹⁸ and R¹⁹ together represent a keto group R²⁰ and R²¹ may together form a carbon-carbon double bond or an epoxy group, R²² then being hydrogen, or R¹⁸ and R²¹ together form a 3,5-cyclo linkage, R¹⁹ and R²⁰ then being hydrogen and R²² being acetoxy; R²³ represents hydrogen or methyl; R²⁴ represents hydrogen or hydroxy and R²⁵ represents acetoxy, or R²⁴ and R²⁵ together represent a keto group.
 23. The compound of claim 22 which is a 14α-fluoroandrost-4-ene-3,17-dione.
 24. The compound of claim 22 which is a 14α-fluorotestosterone.
 25. The compound of claim 22 which is 14α-fluoroprogesterone. 